This application relates to the use of a combination of 10-propargyl-10-deazaminopterin and gemcitabine in the treatment of lymphoma.
10-Propargyl-10-deazaminopterin (“PDX”) is a member of a large class of compounds which have been tested and in some cases found useful in the treatment of tumors. This compound, which has the structure shown in FIG. 1, was disclosed by DeGraw et al., “Synthesis and Antitumor Activity of 10-Propargyl-10-deazaminopterin,” J. Medical Chem. 36: 2228-2231 (1993) and shown to act as an inhibitor of growth in the murine L1210 cell line and to a lesser extent of the enzyme dihydrofolate reductase (“DHFR”). In addition, some results were presented for the antitumor properties of the compound using the E0771 murine mammary tumor model. This data was equivocal because of the small number of mice used in the test (3 per dosage), the absence of any standard deviation information which would quantify the reliability of the data, and the fact that the highest dose used was in fact toxic to the mice. Nevertheless, assuming this data has some predictive value for the efficacy of a drug in treating human tumors, it would at best predict a drug which, at equivalent levels of tolerance, had properties comparable to or perhaps slightly better than methotrexate.
PCT Publication No. WO98/02163, discloses the surprising observation that more highly purified PDX compositions when tested in a xenograft model for their efficacy against human tumors have now been shown to be far superior to methotrexate (“MTX”) and are even superior to edatrexate (“ETX”), a more recent clinical candidate. Moreover, 10-propargyl-10 dAM showed a surprising ability to cure tumors such that there was no evidence of tumor growth several weeks after the cessation of therapy. Thus, highly purified composition containing 10-propargyl-10 dAM. can be used in accordance with the invention to treat tumors, including both solid tumors and leukemias. The composition is illustrated for use in treatment of human mammary tumors and human lung cancer.
Subsequent studies on PDX have shown that it is useful on its own and in combinations with other therapeutic agents. For example, Sirotnak et al., Clinical Cancer Research Vol. 6, 3705-3712 (2000) reports that co-administration of PDX and probenecid, an inhibitor of a cMOAT/MRP-like plasma membrane ATPase greatly enhances the efficacy of PDX against human solid tumors in vivo. PDX and combinations of PDX with platinum based chemotherapeutic agents have been shown to be effective against mesothelioma. (Khokar, et al., Clin. Cancer Res. 7: 3199-3205 (2001).
Gemcitabine (Gem), also referred to as 1-(2′,2′-difluoro-β-D-arabinofuranosyl) cytosine or 2′,2′-difluorodeoxycytidine, is a known compound that belongs to the group of medicines called antimetabolites. It is used to treat various types of cancer, including cancer of the breast, pancreas and lung. Gemcitabine is sold under the tradename GEMZAR.
A variety of in vitro and in vivo experiments have demonstrated that sequential methotrexate (MTX) and cytarabine (Ara-C) are synergistic compared to the single agents or alternative schedules. As early as 1973, Hoovis and Chou demonstrated that MTX and Ara-C exhibited marked synergy in a murine leukemia cell line (L5178Y) when used in a sequence dependent fashion. (Hoovis M L, Chou M Y. Enhancement of the antiproliferative action of 1- -D-arabinofuranosylcytosine by methotrexate in murine leukemic cells (L5178Y). Cancer Res. 1973; 33:521-5.). The authors demonstrated that the pretreatment with MTX significantly increased the level of ara-CTP independent of DNA synthesis, which led to increased incorporation into RNA, and enhanced cytotoxicity. Cadman and Eiferman, Mechanism of synergistic cell killing when methotrexate precedes cytosine arabinoside: study of L1210 and human leukemic cells. J. Clin. Invest. 1979; 64:788-97, similarly demonstrated the sequence dependency of MTX and Ara-C in the L1210 model of myeloid leukemia, confirming the preferential accumulation of ara-CTP in MTX pretreated cells. Using the classic isobologram method of Steel and Peckham, Akutsu et al., Schedule-dependent synergism and antagonism between methotrexate and cytarabine against human leukemia cell lines in vitro. Leukemia 2002; 16:1808-17, recently demonstrated that the ordered treatment of MTX followed by Ara-C is truly synergistic in a mathematical analysis, while other schedules of administration (for example, given together) were potentially antagonistic. MTX followed by Ara-C is currently a treatment of choice for lymphoma.